Altered AP-1, RUNX and EGR chromatin dynamics drive fibrotic lung disease.

Pulmonary fibrosis, including systemic sclerosis-associated interstitial lung disease (SSc-ILD), involves myofibroblasts and SPP1 macrophages as drivers of fibrosis. Single-cell RNA sequencing has delineated fibroblast and macrophages transcriptomes, but limited insight into transcriptional control of profibrotic gene programs. To address this challenge, we analyzed multiomic snATAC/snRNA-seq on explanted SSc-ILD and donor control lungs.

Convergent and divergent immune aberrations in COVID-19, post-COVID-19-interstitial lung disease, and idiopathic pulmonary fibrosis.

We aimed to study transcriptional and phenotypic changes in circulating immune cells associated with increased risk of mortality in COVID-19, resolution of pulmonary fibrosis in post-COVID-19-interstitial lung disease (ILD), and persistence of idiopathic pulmonary fibrosis (IPF). Whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from 227 subjects with COVID-19, post-COVID-19 interstitial lung disease (ILD), IPF, and controls. We measured a 50-gene signature (nCounter, Nanostring) previously found to be predictive of IPF and COVID-19 mortality along with plasma levels of several biomarkers by Luminex.

Development and validation of a mortality risk prediction model for chronic obstructive pulmonary disease: a cross-sectional study using probabilistic graphical modelling.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of mortality. Predicting mortality risk in patients with COPD can be important for disease management strategies. Although all-cause mortality predictors have been developed previously, limited research exists on factors directly affecting COPD-specific mortality.

A hybrid constrained continuous optimization approach for optimal causal discovery from biological data.

Motivation: Understanding causal effects is a fundamental goal of science and underpins our ability to make accurate predictions in unseen settings and conditions. While direct experimentation is the gold standard for measuring and validating causal effects, the field of causal graph theory offers a tantalizing alternative: extracting causal insights from observational data. Theoretical analysis has shown that this is indeed possible, given a large dataset and if certain conditions are met.

The transcriptome of CD14 CD163 HLA-DR monocytes predicts mortality in Idiopathic Pulmonary Fibrosis.

Rationale: The association between immune-cell-specific transcriptomic profiles and Idiopathic Pulmonary Fibrosis (IPF) mortality is unknown.

Objectives: To determine immune-cell-specific transcriptomic profiles associated with IPF mortality.

Methods: We profiled peripheral blood mononuclear cells (PBMC) in 18 participants [University of South Florida: IPF, COVID-19, post-COVID-19 Interstitial Lung Disease (Post-COVID-19 ILD), controls] by single-cell RNA sequencing (scRNA-seq) and identified 16 immune-cell-specific transcriptomic profiles.

Identification of factors directly linked to incident chronic obstructive pulmonary disease: A causal graph modeling study.

Background: Beyond exposure to cigarette smoking and aging, the factors that influence lung function decline to incident chronic obstructive pulmonary disease (COPD) remain unclear. Advancements have been made in categorizing COPD into emphysema and airway predominant disease subtypes; however, predicting which healthy individuals will progress to COPD is difficult because they can exhibit profoundly different disease trajectories despite similar initial risk factors. This study aimed to identify clinical, genetic, and radiological features that are directly linked-and subsequently predict-abnormal lung function.

Cellular and transcriptional profiles of peripheral blood mononuclear cells pre-vaccination predict immune response to preventative MUC1 vaccine.

A single arm trial (NCT007773097) and a double-blind, placebo controlled randomized trial ( NCT02134925 ) were conducted in individuals with a history of advanced colonic adenoma to test the safety and immunogenicity of the MUC1 tumor antigen vaccine and its potential to prevent new adenomas. These were the first two trials of a non-viral cancer vaccine administered in the absence of cancer. The vaccine was safe and strongly immunogenic in 43% (NCT007773097) and 25% ( NCT02134925 ) of participants.

Pre-vaccination transcriptomic profiles of immune responders to the MUC1 peptide vaccine for colon cancer prevention.

Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine.

The Florida Scoring System for stratifying children with suspected Sjögren's disease: a cross-sectional machine learning study.

Background: Childhood Sjögren's disease is a rare, underdiagnosed, and poorly-understood condition. By integrating machine learning models on a paediatric cohort in the USA, we aimed to develop a novel system (the Florida Scoring System) for stratifying symptomatic paediatric patients with suspected Sjögren's disease.

Methods: This cross-sectional study was done in symptomatic patients who visited the Department of Pediatric Rheumatology at the University of Florida, FL, USA.

Disentangling Predictors of COPD Mortality with Probabilistic Graphical Models.

Background-research Question: Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of mortality. Predicting mortality risk in COPD patients can be important for disease management strategies. Although scores for all-cause mortality have been developed previously, there is limited research on factors that may directly affect COPD-specific mortality.

Lung Epithelium Releases Growth Differentiation Factor 15 in Response to Pathogen-mediated Injury.

GDF15 (growth differentiation factor 15) is a stress cytokine with several proposed roles, including support of stress erythropoiesis. Higher circulating GDF15 levels are prognostic of mortality during acute respiratory distress syndrome, but the cellular sources and downstream effects of GDF15 during pathogen-mediated lung injury are unclear. We quantified GDF15 in lower respiratory tract biospecimens and plasma from patients with acute respiratory failure.

A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-related hepatitis.

Unlabelled: Alcohol-related hepatitis (AH) is plagued with high mortality and difficulty in identifying at-risk patients. The extracellular matrix undergoes significant remodeling during inflammatory liver injury that can be detected in biological fluids and potentially used for mortality prediction. EDTA plasma samples were collected from AH patients (n= 62); Model for End-Stage Liver Disease (MELD) score defined AH severity as moderate (12-20; n=28) and severe (>20; n=34).

CellularPotts.jl: simulating multiscale cellular models in Julia.

Summary: CellularPotts.jl is a software package written in Julia to simulate biological cellular processes such as division, adhesion, and signaling. Accurately modeling and predicting these simple processes is crucial because they facilitate more complex biological phenomena related to important disease states like tumor growth, wound healing, and infection.

LEF1 isoforms regulate cellular senescence and aging.

The study of aging and its mechanisms, such as cellular senescence, has provided valuable insights into age-related pathologies, thus contributing to their prevention and treatment. The current abundance of high-throughput data combined with the surge of robust analysis algorithms has facilitated novel ways of identifying underlying pathways that may drive these pathologies. For the purpose of identifying key regulators of lung aging, we performed comparative analyses of transcriptional profiles of aged versus young human subjects and mice, focusing on the common age-related changes in the transcriptional regulation in lung macrophages, T cells, and B immune cells.

Defining trophoblast injury patterns in the transcriptomes of dysfunctional placentas.

Trophoblast injury is central to clinically relevant placenta dysfunction. We hypothesized that the mRNA of primary human trophoblasts, exposed to distinct injuries in vitro, capture transcriptome patterns of placental biopsies obtained from common obstetrical syndromes. We deployed a CIBERSORTx deconvolution method to correlate trophoblastic RNAseq-based expression matrices with the transcriptome of omics-defined placental dysfunction patterns in vivo.

Prognostic Insights from Longitudinal Multicompartment Study of Host-Microbiota Interactions in Critically Ill Patients.

Critical illness can disrupt the composition and function of the microbiome, yet comprehensive longitudinal studies are lacking. We conducted a longitudinal analysis of oral, lung, and gut microbiota in a large cohort of 479 mechanically ventilated patients with acute respiratory failure. Progressive dysbiosis emerged in all three body compartments, characterized by reduced alpha diversity, depletion of obligate anaerobe bacteria, and pathogen enrichment.

Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells.

Human regulatory T cells (T) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of T for cancer therapy without affecting immune homeostasis. Identifying pathways that may distinguish tumor-restricted T is important, yet the transcriptional programs that control intratumoral T gene expression, and that are distinct from T in healthy tissues, remain largely unknown.

Transcriptional changes of the aging lung.

Aging is a natural process associated with declined organ function and higher susceptibility to developing chronic diseases. A systemic single-cell type-based study provides a unique opportunity to understand the mechanisms behind age-related pathologies. Here, we use single-cell gene expression analysis comparing healthy young and aged human lungs from nonsmoker donors to investigate age-related transcriptional changes.

Integrated unbiased multiomics defines disease-independent placental clusters in common obstetrical syndromes.

Background: Placental dysfunction, a root cause of common syndromes affecting human pregnancy, such as preeclampsia (PE), fetal growth restriction (FGR), and spontaneous preterm delivery (sPTD), remains poorly defined. These common, yet clinically disparate obstetrical syndromes share similar placental histopathologic patterns, while individuals within each syndrome present distinct molecular changes, challenging our understanding and hindering our ability to prevent and treat these syndromes.

Methods: Using our extensive biobank, we identified women with severe PE (n = 75), FGR (n = 40), FGR with a hypertensive disorder (FGR + HDP; n = 33), sPTD (n = 72), and two uncomplicated control groups, term (n = 113), and preterm without PE, FGR, or sPTD (n = 16).

Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care.